Despite much progress in recent years towards the characterization of functional regions of HIV-1 Envelope protein (Env) and in defining major neutralizing epitopes, progress towards an HIV-I vaccine capable of inducing a protective Immoral response has been limited (Zolla-Pazner et al. (2004) Nat. Rev. Immunol. 4(3):199-210; Burton et al. (2004) Nat. Rev. Immunol. 5(3):233-236). There is now a realization that typical antibodies generated in response to infection or immunization with standard Env proteins do not possess appreciable neutralizing activities for common clinical or primary HIV-1 isolates, even when these antibodies are directed against neutralization epitopes present in the target viruses. One mechanism for this resistance appears to be the shielding of sensitive neutralization domains in intact virions by specific regions and structural features of HIV-1 clinical isolate SU (HIV-1 SU), located in the V1/V2 region (Pinter at al. (2004) J. Virol. 78(10):5205-5215). The highly effective masking of sensitive neutralization sites by the V1/V2 domain poses a major conundrum for HIV-1 vaccine development. The limited number of known neutralization targets that are insensitive to such masking, are poorly immunogenic. A few exceptional monoclonal antibodies (mAbs) have been identified that are not sensitive to such effects and possess broad neutralizing activities for primary isolates. These include the HIV-1 gp120-specific mABs b12 and 2G12 (Burton et al. (2004) Nat. Rev. Immunol. 5(3):233-236), and gp41-specific mAbs 2F5 and 4E10 (Zwick et al. (2001) 75(22):10892-10905; Mined et al. (2004) AIDS Res. Hum. Retroviruses 20(7):755-762). However, these mAbs possess unusual structures, including unusually large CDR3 regions or have autoreactive properties (Haynes et al., (2005) Science 308(5730):1906-1908), and antibodies against these epitopes are rarely produced in immunized or infected individuals.
Thus, it is important to identify additional immunogenic targets that can mediate potent neutralization, while also being reasonably well conserved or present in a limited number of allelic forms that can be formulated into a multivalent vaccine.